The present invention relates to a solid pharmaceutical preparation for dialysis and, more particularly, to a solid dialysate concentrate for preparing a dialysis solution containing sodium hydrogencarbonate and a process for producing the same.
When hemodialysis is carried out for a patient suffering from weakened hepatic function, the blood of the patient is cleaned in an artificial kidney. Generally, a dialysis solution is perfused in this artificial kidney and contacted via a dialysis membrane with the blood of the patient so that wastes in the blood are transferred to the dialysis solution. As this dialysis solution, an acetate dialysis solution has been used widely but has recently been substituted with a dialysis solution containing sodium hydrogencarbonate (i.e., sodium bicarbonate) drastically reducing unpleasant symptoms during dialysis.
The dialysis solution containing sodium bicarbonate is usually prepared from two kinds of dialysis solution, that is, a pharmaceutical preparation (referred to hereinafter as composition A) containing electrolytes (e.g. sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium acetate) and a pH adjusting agent (e.g., acetic acid) and a pharmaceutical preparation (referred to hereinafter as composition B) containing sodium bicarbonate. These dialysis solutions may contain sugars such as glucose or may be mixed with another pharmaceutical preparation containing sugars.
Heretofore, compositions A and B were commercialized in the form of a concentrated solution prepared at a predetermined concentration and used by the customer after being diluted with water. However, about 300 L perfusion solution of sodium hydrogencarbonate is necessary for the dialysis of one patient, and thus in conducting dialysis treatment of a large number of patients, a large quantity of the concentrated solution must be used and diluted with water. Accordingly, there are recently many cases where composition B prepared in a powdery form is used to reduce the burden on those who prepare the dialysis solution and to reduce storage space. In this connection, a pharmaceutical preparation for dialysis consisting of two pulverized compositions, one of which is a pulverized composition A and the other of which is pulverized composition B, and a solid pharmaceutical preparation for dialysis consisting of all ingredients necessary for dialysis as one composition, namely a granulated or powdered solid dialysate concentrate, have also been developed.
As the one composition type of solid pharmaceutical preparation for dialysis, there are disclosed those obtained by mixing all ingredients necessary for a dialysis solution in the form of granules or powders, or by coating essential ingredients on a nucleating particle (Japanese Patent No. 2846883, Japanese Patent No. 2739898 and JP-A 10-259133). However, these pharmaceutical preparations suffer from the problem that since sodium bicarbonate, calcium salt and magnesium salt are directly contacted with one another, these ingredients react with crystallization water contained in the calcium salt and magnesium salt, or with moisture in the air, to form sparingly soluble salts. In addition, there is another problem that since sodium bicarbonate and acetic acid are directly contacted with each other, these ingredients react with each other to generate carbon dioxide, with the result that the pH of the dialysis solution can not be maintained in a suitable range (Japanese Patent No. 2846883 and Japanese Patent No. 2739898).
On one hand, a solid pharmaceutical preparation for dialysis comprising sodium bicarbonate in an innermost layer and sodium diacetate as an acid in an outermost layer (JP-A 10-259133) may generate carbon dioxide upon decomposition of sodium bicarbonate in the innermost layer by heat or water added in later steps. Further, the water and heat generated from the decomposition of sodium bicarbonate cause decomposition of glucose in the solid pharmaceutical preparation for dialysis. Moreover, acetic acid which has been bound to sodium acetate in sodium diacetate is easily released therefrom, and this acetic acid reacts with sodium bicarbonate to generate carbon dioxide and then the pH of the dialysis solution can not be maintained in a suitable range.
In consideration of these disadvantages, some solid pharmaceutical preparations for dialysis consisting of all ingredients necessary for dialysis as one composition are developed. In one pharmaceutical preparation, sodium bicarbonate and an organic acid, or sodium bicarbonate and calcium salt or magnesium salt are layered such that both of them are not contacted with each other and reaction therebetween is prevented (JP-A 6-335527, JP-A 8-169836, JP-A 8-92071 and JP-A 11-114054). Another solid pharmaceutical preparation for dialysis consisting of all ingredients necessary for dialysis as one composition is produced by granulating calcium salt, magnesium salt and solid organic acid together, but separately granulating sodium bicarbonate, and then mixing the above granulated ingredients and the granulated sodium bicarbonate (JP-A 6-335528 and JP-A 8-92070).
In these solid pharmaceutical preparations for dialysis, however, it is likely that if pH adjusting agents, i.e., a solid organic acid, and sodium acetate are contacted with each other, the solid organic acid reacts with sodium acetate to form free acetic acid, and the vaporized acetic acid reacts with sodium bicarbonate to generate carbon dioxide. Further, the respective ingredients to be coated on nucleating particles of electrolytes in the solid pharmaceutical preparations for dialysis must be finely pulverized by a sample mill and as a result, not only the steps but also the time for producing the preparation are increased. Additionally, a solid pharmaceutical preparation for dialysis having an outermost layer, which under drying and by spraying with water or an aqueous solution, has been coated with a fine powder obtained by pulverizing a mixture of sodium bicarbonate, sodium chloride and other electrolytes (JP-A 11-114054), contains a large amount of the powder and requires a longer time for coating and drying thereof such that the sodium bicarbonate may be decomposed by prolonged heating.
In addition, there is also known a solid pharmaceutical preparation for dialysis consisting of all ingredients prepared by mixing calcium salt, magnesium salt, solid organic acid, sodium bicarbonate and glucose coated respectively with sodium citrate (JP-A 10-87478), or a solid pharmaceutical preparation for dialysis consisting of all ingredients prepared by mixing calcium salt, magnesium salt, solid organic acid and sodium bicarbonate coated respectively with sodium chloride and/or potassium chloride (JP-A 10-330270). However, it is difficult to attain uniformity of the ingredients in the solid pharmaceutical preparations for dialysis because the solid organic acid as an ingredient added in a small amount, the calcium salt and magnesium salt are respectively mixed in the form of powder.
Under these circumstances as described above, the object of the present invention is to provide a solid pharmaceutical preparation for dialysis consisting of all ingredients as one composition, which is excellent in the uniformity of the ingredients therein, is capable of preventing not only a reaction between sodium bicarbonate and a solid organic acid, or sodium bicarbonate and electrolytes, but also a reaction between a solid organic acid and sodium acetate, and does not require further pulverization of the ingredients.
As a result of their eager study for solving the problems described above, the present inventors have found that a solid pharmaceutical preparation for dialysis which comprises a granule or powder with a plurality of layers of sodium acetate, solid organic acid and sodium bicarbonate separated respectively and preferably, which are coated with glucose and sodium bicarbonate in the form of non-pulverized crystals therein, achieves the intended object, thus arriving at the present invention.
That is, the present invention relates to a solid pharmaceutical preparation for dialysis comprising an electrolyte for hemodialysis, a solid organic acid and glucose and is characterized by comprising a plurality of layers which are separated from each other on the surface of a nucleating particle consisting of sodium chloride, wherein the plurality of layers include a layer (A) comprising sodium acetate but not containing the solid organic acid, a layer (B) comprising the solid organic acid but not containing sodium acetate, and a layer (C) comprising sodium bicarbonate.
Further, the present invention relates to a process for producing a pharmaceutical preparation for dialysis, which comprises forming a layer (A) containing sodium acetate but not containing solid organic acid on the surface of a nucleating particle, and forming a layer (B) containing solid organic acid and separated from the layer (A) on the surface of the nucleating particle, and forming a layer (C) containing sodium bicarbonate and separated from the layer (B) on the surface of the nucleating particle in this order.
In one embodiment of the present invention, the solid pharmaceutical preparation for dialysis comprises a nucleating particle consisting of sodium chloride, a first layer formed on said nucleating particles and containing sodium acetate but not containing a solid organic acid as layer (A), a second layer containing at least one compound selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium chloride but not containing sodium acetate or a solid organic acid, a third layer containing a solid organic acid but not containing sodium acetate as layer (B), a fourth layer containing glucose powder and a fifth layer containing sodium bicarbonate powder as layer (C) in this order.
One embodiment of the process in the present invention comprises,
(a) spraying an aqueous solution containing sodium acetate but not containing a solid organic acid on the surface of nucleating particles consisting of sodium chloride, and drying the particles,
(b) spraying the particles obtained in step (a) with an aqueous solution containing at least one compound selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium chloride but not containing sodium acetate and not containing a solid organic acid, and drying the particles,
(c) spraying the particles obtained in step (b) with an aqueous solution containing a solid organic acid and not containing sodium acetate and drying the particles,
(d) mixing glucose powder with the particles obtained in step (c), then spraying the particles with an aqueous solution containing glucose and/or sodium chloride and drying the particles,
(e) mixing sodium bicarbonate powder with the particles obtained in step (d), then spraying the particles with an aqueous solution containing glucose and/or sodium chloride and drying the particles.